UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Elorza, Álvaro A.; Hyde, Brigham B.; Mikkola, Hanna; Collins, Sheila; Shirihai, Orian S.

doi:10.1074/jbc.m805400200

Cited by 30 publications

(26 citation statements)

References 65 publications

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“…Previously, we and other research groups have reported that UCP2 is expressed in haematopoietic and human pluripotent stem cells [15], [19], [20]. To confirm the common expression of UCP2 in stem cells, we now tested the protein abundance in mESCs.…”

Section: Resultsmentioning

confidence: 99%

Uncoupling Protein 2 and 4 Expression Pattern during Stem Cell Differentiation Provides New Insight into Their Putative Function

et al. 2014

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Apart from the first family member, uncoupling protein 1 (UCP1), the functions of other UCPs (UCP2-UCP5) are still unknown. In analyzing our own results and those previously published by others, we have assumed that UCP's cellular expression pattern coincides with a specific cell metabolism and changes if the latter is altered. To verify this hypothesis, we analyzed the expression of UCP1-5 in mouse embryonic stem cells before and after their differentiation to neurons. We have shown that only UCP2 is present in undifferentiated stem cells and it disappears simultaneously with the initiation of neuronal differentiation. In contrast, UCP4 is simultaneously up-regulated together with typical neuronal marker proteins TUJ-1 and NeuN during mESC differentiation in vitro as well as during murine brain development in vivo. Notably, several tested cell lines express UCP2, but not UCP4. In line with this finding, neuroblastoma cells that display metabolic features of tumor cells express UCP2, but not UCP4. UCP2's occurrence in cancer, immunological and stem cells indicates that UCP2 is present in cells with highly proliferative potential, which have a glycolytic type of metabolism as a common feature, whereas UCP4 is strongly associated with non-proliferative highly differentiated neuronal cells.

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Section: Resultsmentioning

confidence: 99%

Uncoupling Protein 2 and 4 Expression Pattern during Stem Cell Differentiation Provides New Insight into Their Putative Function

et al. 2014

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“…As ABC-meÀ/À erythroid cells show an increase in mitochondrial superoxide, a superoxide dismutase 2 (SOD2) mimetic compound (MnTBAP) was used to reduce mitochondrial superoxide levels. 17 Isolated blood cells from day 10.5 pc embryos were differentiated in a hematopoietic semi-solid media (see Materials and Methods). The number of the (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

“…Samples were obtained after differentiation of these colonies and apoptosis was analyzed using flow cytometry (TUNEL-BrdU, as described below for embryonic blood) and also for hemoglobin content by measuring absorbance (after lysis of colonies) as previously described. 6,17 Fluorescence-activated cell sorting (FACS) analysis. Isolated embryonic blood from day 10.5 pc (B1 Â 10 5 ) was immunostained simultaneously with PE-conjugated anti-TER119 (1 : 100) (BD Pharmingen, San Diego, CA, USA) and FITC-conjugated anti-CD71 (Transferrin receptor) (1 : 100; BD Pharmingen).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

et al. 2012

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The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-meÀ/À mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-meÀ/À erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-meÀ/À erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-meÀ/À erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. Cell Death and Differentiation (2012) 19, 1117-1126 doi:10.1038/cdd.2011; published online 13 January 2012A central event during erythroid development is the induction of the components responsible for heme biosynthesis. Although heme is also produced in non-erythroid cells, its biosynthesis is specifically regulated during erythroid differentiation. 1-3 Thus, mutations in some specific genes involved in heme production have been shown to cause several human blood disorders, such as sideroblastic anemias. 4 This type of anemia is characterized by abnormal erythroid differentiation with a reduction in the total number of erythrocytes. 4 In addition, there are idiopathic anemias (either genetic or druginduced) in which the primary molecular defect is unknown. Recently, a novel bioinformatic approach identified new genes involved in heme biosynthesis that could be potential therapeutic targets for these disorders. 5 Furthermore, this large-scale computational screen identified again the ATP Binding Cassette mitochondrial erythroid transporter (ABCme/ABCB10) as an important protein for heme biosynthesis. 5 We previously identified ABC-me as a downstream target of an essential transcription factor for terminal erythroid differentiation, namely GATA-1. 6 ABC-me is a homodimeric transporter located in the inner mitochondrial membrane, which shows the highest expression levels in erythroid tissues. 6,7 Importantly, during early stages of mouse development (day 10 post coitus, pc), ABC-me expression is detected exclusively at the primitive sites of hematopoiesis, namely the yolk sac blood islands. 6 Furthermore, at day 9.5-10.5 pc,...

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“…Expression of UCP2 gene occurs at early stages of erythroid maturation (when cells are not fully committed to heme biosynthesis), and high levels of UCP2 protein were found in erythroid cells. Detailed analysis of bone marrow and fetal liver progenitor cells, in vitro and in vivo , revealed that UCP2 deficiency led to a significant decrease in cell proliferation at the Epo‐dependent phase of erythropoiesis, without affecting heme biosynthesis (112). This is an interesting finding indicating that UCP2 is another regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.…”

Section: Key Regulators Of Erythropoiesis: Iron Homeostasis‐cellular mentioning

confidence: 99%

Erythropoiesis: Model systems, molecular regulators, and developmental programs

2009

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SummaryHuman erythropoiesis is a complex multistep developmental process that begins at the level of pluripotent hematopoietic stem cells (HSCs) at bone marrow microenvironment (HSCs niche) and terminates with the production of erythrocytes (RBCs). This review covers the basic and contemporary aspects of erythropoiesis. These include the: (a) cell-lineage restricted pathways of differentiation originated from HSCs and going downward toward the blood cell development; (b) model systems employed to study erythropoiesis in culture (erythroleukemia cell lines and embryonic stem cells) and in vivo (knockout animals: avian, mice, zebrafish, and xenopus); (c) key regulators of erythropoiesis (iron, hypoxia, stress, and growth factors); (d) signaling pathways operating at hematopoietic stem cell niche for homeostatic regulation of self renewal (SCF/c-kit receptor, Wnt, Notch, and Hox) and for erythroid differentiation (HIF and EpoR). Furthermore, this review presents the mechanisms through which transcriptional factors (GATA-1, FOG-1, TAL-1/ SCL/MO2/Ldb1/E2A, EKLF, Gfi-1b, and BCL11A) and miRNAs regulate gene pattern expression during erythroid differentiation. New insights regarding the transcriptional regulation of a-and b-globin gene clusters were also presented. Emphasis was also given on (i) the developmental program of erythropoiesis, which consists of commitment to terminal erythroid maturation and hemoglobin production, (two closely coordinated events of erythropoieis) and (ii) the capacity of human embryonic and umbilical cord blood (UCB) stem cells to differentiate and produce RBCs in culture with highly selective media. These most recent developments will eventually permit customized red blood cell production needed for transfusion.

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UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Cited by 30 publications

References 65 publications

Uncoupling Protein 2 and 4 Expression Pattern during Stem Cell Differentiation Provides New Insight into Their Putative Function

Uncoupling Protein 2 and 4 Expression Pattern during Stem Cell Differentiation Provides New Insight into Their Putative Function

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

Erythropoiesis: Model systems, molecular regulators, and developmental programs

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